The Spectrum of Triple-Negative Breast Disease: High- and Low-Grade Lesions

Abstract

Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, most triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histologic, and clinical differences, with neoplasms in this group ranging from low to high grade. Among the less common low-grade triple-negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbors the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility. Progression to high-grade triple-negative breast cancer likely occurs in both subgroups but at different rates. In this review, we describe the heterogeneity of triple-negative disease, focusing on the histologic and molecular features of the low-grade lesions. Recognition that triple-negative breast cancer is an operational term and that triple-negative disease is heterogeneous and includes low-grade forms driven by distinct sets of genetic alterations is germane to the successful implementation of precision medicine.

Figure 1

Low-grade and high-grade histologic types of triple-negative breast carcinomas (TNBCs). Representative micrographs of low-grade and high-grade variants of TNBC. Several histologic types of low-grade TNBC, including salivary gland–like tumors of the breast and solid papillary carcinoma with reverse polarity, are underpinned by specific/pathognomonic genetic alterations. In contrast, acinic cell carcinoma and high-grade variants of TNBC have somatic genomic landscape similar to those of conventional TNBC. Their genetic alterations are compared with those reported for common forms of TNBC. Low-grade variants of metaplastic breast carcinomas (MBCs) are unlikely to be underpinned by specific genetic alterations; however, the genetic analyses performed to date included only a few or single cases. Progression to high-grade TNBC has been described in most low-grade forms of TNBC; however, it occurs at a different rate. Whereas fairly common in acinic cell carcinoma, it is a rare event in the salivary gland–like tumors of the breast and solid papillary carcinoma with reverse polarity. ∗It should be noted that evidence for the presence of PRKD1 E710D mutations or PRKD1/2/3 rearrangements in polymorphous carcinoma of the breast remains to be documented. Original magnification, ×200. PI3K, phosphatidylinositol 3-kinase.

Figure 2

Low-grade triple negative breast neoplasia family. Representative micrographs of microglandular adenosis (MGA) and associated lesions (A, B, and C) and an acinic cell carcinoma (ACC) (D, E, and F), lesions comprising the low-grade triple-negative breast neoplasia family, grouped together based on their histologic, immunophenotypic, and genetic overlap. It comprises MGA and atypical MGA, which are nonobligate precursors of high-grade triple-negative breast carcinoma (TNBC), and ACC, which is characterized by diffuse expression of serous differentiation markers, such as lysozyme, and frequently progresses to high-grade TNBC. A: MGA is shown. B: MGA is shown in the bottom left corner, whereas MGA-associated invasive TNBC is shown in the top right corner. C: Atypical MGA is shown. D: Low-grade ACC is shown. E: ACC is shown on the right, whereas an associated high-grade TNBC is shown on the left. The inset shows lysozyme expression in the TNBC component. F: Lysozyme expression is shown in a low-grade ACC. The lesions comprising the low-grade triple-negative neoplasia family have a somatic genomic landscape indistinguishable from common forms of TNBC, despite the low-grade morphologic features and indolent behavior. Original magnification: ×200 (A, C, D, E, inset, and F); ×40 (B); ×20 (E).